The normal function of the immune system is essential for health, and dysfunction of the immune system leads to myriad diseases. For example, deficiency of immune cell production or defective immune cell function can lead to a wide spectrum of immunodeficiency diseases, and overactivity of various components of the immune system leads to the development of allergic or autoimmune diseases.
Four major components of the immune system participate in host defense and in pathogenesis of autoimmune diseases: 1) humoral immunity involving B cells, 2) cell-mediated immunity involving T cells and monocytes, 3) phagocytic cells of the reticuloendothelial system involving macrophages and polymorpho leukocytes, and 4) complement. Defects in antibody production generally result in recurrent bacterial infections. Defects in cellular immunity result in viral, mycobacterial and fungal infections, an extreme example being acquired immunodeficiency syndrome (AIDS). Disorders of phagocyte function are manifested by recurrent skin infections and deficiencies of early and late complement components are associated with autoimmune phenomena.
Sepsis is a response to infection caused by any class of microorganism including, but not limited to gram-negative and gram-positive bacteria, fungi, mycobacteria, viruses or protozoans. As sepsis progresses to septic shock, the risk of dying increases substantially. Sepsis results from complex interactions among microbial molecules, leukocytes, humoral factors, the vascular endothelial cytokines, and thromboxanes.
Current therapies for allergic, autoimmune and inflammatory diseases involve the use of nonspecific immune-modulating or immunosuppressive agents, for example, glucocorticoids or cytotoxic drugs. The goal of development of new treatments for immune-mediated diseases is to design ways to specifically interrupt pathologic immune responses, leaving nonpathologic immune responses intact. For example, the burst of reactive oxidants .cndot.O.sub.2.sup.-, H.sub.2 O.sub.2, OCl.sup.- and NO from white blood cells in response to bacterial and virus infections is of immediate survival value, but these oxidants have deleterious consequences in damaging DNA and leading to hyperproliferation. Weitzman, S. A. and Gordon, L. J., 1990, Blood 76: 655.
2.1 Allergic Diseases
The immune response in allergic diseases involves antigen recognition, humoral and cellular effector mechanisms and inflammatory reactions to environmental antigens, the inflammatory reactions being responsible in causing the deleterious effects. Some examples of allergic diseases are asthma, allergic rhinitis, eczema, atopic dermatitis and allergic contact dermatitis.
2.2 Autoimmune Diseases
Autoimmune disease is characterized by production of either antibodies that react with host tissue or immune effector T cells that are autoreactive to endogenous self peptides. Some examples of autoimmune disorders are rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, immune thrombocytopenic purpura, myasthenia gravis, ulcerative colitis, Crohn's disease, scleroderma and psoriasis.
Traditionally, the main approach of treating autoimmune diseases consisted of compounds which were designed to suppress the immune system. Verma, X. et. al., 1992, Canadian J. Neurol. Sci. 19: 360-375. These compounds include steroids, cyclophosphamide, azathioprine and anti-thymocyte globulin. Another treatment modality that has been used is therapeutic plasma exchange which consists of extracting the patient's blood, separating the plasma, and replacing it with donor plasma or plasma constituents. For some patients, protein A may be useful in treating autoimmune diseases. Wiesenhutter, X. et. al., 1994, J. Rheumatol. 21: 804-812.
2.3 Septic Shock
Septic shock or endotoxin shock is a pathophysiologic phenomenon resulting from the release of endotoxin from gram-negative organisms. Endotoxins are lipopolysaccharide protein lipid complexes which are released from cell membranes of killed bacteria. The most common are Escherichia coli, Aerobacter aerogenis, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeroginosa, Proteus species, Pseudomonas species, Bacteroides species and Salmonella species. The underlying pathophysiological process of septic or endotoxin shock appears to have an immunological basis involving the release of vasoactive substances and neurohumoral agents, and precipitation of coagulation abnormalities.
Treatment of septic shock is directed primarily toward establishing a specific microbial diagnosis and an entry site for the responsible microorganisms. Therapy involves use of antibiotics, glucocorticoids and necessary surgical intervention to drain abscesses or to remove infected foreign bodies. Sheagren, J. N., 1981, N. Engl. J. Med., 305: 456; and Pathophysiology--The Biological Principles of Disease, ed. L. M. Smith and S. O. Thier, W. B. Saunders Company (1985) 164-172.
2.4 Magnesium
Magnesium is an important element for health and disease. It is primarily found within the cell, where it is a cofactor for over 300 enzymatic reactions in energy metabolism, and protein and nucleic acid synthesis. Magnesium deficiency may cause weakness, tremors, seizures, cardiac arrhythmias, hypokalemia, and hypocalcemia. The causes of hypomagnesemia are reduced intake, for example, poor nutrition or intravenous fluids without magnesium; reduced absorption, for example, chronic diarrhea, malabsorption, or bypass/resection of bowel; redistribution, for example, exchange transfusion or acute pancreatitis; and increased excretion, for example, medication, alcoholism, renal tubular disorders, hypercalcemia, hyperthyroidism, aldosteronism, stress or excessive lactation. A large segment of the U.S. population may have an inadequate intake of magnesium and may have a chronic latent magnesium deficiency. The ideal intake of magnesium for an adult is 15 to 20 mmol/d (36 to 48 mg/d). Magnesium is absorbed primarily in the jejunum and ileum, and healthy persons absorb about 30 to 40 percent of ingested magnesium. The majority of adults have a dietary intake of magnesium less than the recommended dietary intake (RDI) in the range of 43.3% to 93.0% of RDI. Pao, E. M., Mickle, S. J., 1981, Food Technol. 35: 58-69.